The compounds of the instant invention are fully described in copending U.S. application Ser. No. 08/223,932 filed Apr. 13, 1994 now U.S. Pat. No. 5,491,172. The use of the compounds taught is hypercholesterolemia and atherosclerosis. This application is hereby incorporated by reference.
The compounds of the copending application show increased chemical stability over those of U.S. Pat. No. 5,245,068.
The present invention relates generally to lipoprotein(a), Lp(a), and more particularly to methods and agents to lower its plasma concentrations to achieve therapeutic benefit.
The macromolecule known as lipoprotein(a), or Lp(a), is a complex of low-density lipoproteins (LDL), and a hydrophilic glycoprotein that has been given the name apolipoprotein(a), or apo(a). The principal protein of LDL is apo B-100, and apo(a) is attached to the apo B moiety of LDL by a disulfide bond. LDL is the major transporter of cholesterol in human plasma. The physiological function of Lp(a) is unknown.
Apo(a) is not similar in structure to other apolipoproteins but exhibits similarity to another plasma protein called plasminogen. The structure of plasminogen includes five tandemly repeated homologous domains called kringles (Kringles I-V), which are pretzel-like structures stabilized by three internal disulfide bridges followed by a protease domain. Kringle structures have been identified in various other proteins such as prothrombin, tissue-type plasminogen activator (t-PA), urokinase and coagulation Factor XII (Utermann, Science, 1989;246:904-910). Apo(a) lacks kringles similar to I to III of plasminogen but has multiple copies of the kringle domain similar to the fourth one of plasminogen, and a single copy of a kringle domain similar to the fifth one of plasminogen (kringle-5). Apo(a) also contains a protease domain.
Lp(a) was first identified by Berg in 1963 (Berg, Acta Pathol. Microbiol. Scand., 1963;59:369) as an antigenic activity associated with the LDL fraction in the plasma of some individuals. Plasma Lp(a) levels vary in different individuals from less than 2 mg/dL to greater than 200 mg/dL. Increased plasma Lp(a) levels are considered to be a risk factor for atherosclerosis, either alone or in conjunction with elevated LDL levels (Kostner, et al., Circulation, 1989;80(5):1313-1319 citing previous investigators) The plasma concentration of Lp(a) and the size of apo(a) are genetically determined (Gavish, et al., J. Clin. Invest., 1989;84:2021-2027).
The discovery of the homology of apo(a) to plasminogen has prompted further investigation as to the role played by Lp(a). Hajjar, et al., Nature, 1989;339:303-305 considered the similarity between the apo(a) component of Lp(a) and plasminogen and investigated the effect that Lp(a) might have on the interaction between plasminogen and the endothelial cell, and found that Lp(a) competed for plasminogen binding sites and appeared to be capable of inhibiting the activation of plasminogen on the surface of endothelial cells by t-PA. This suggests that elevated levels of Lp(a) might impair and inhibit cell surface fibrinolysis, thus interfering with the fibrinolytic system. In Kostner, et al. (vide supra), HMG-COA reductase inhibitors such as simvastatin and lovastatin, as well as other known cholesterol-lowering agents were administered to a test group of patients, and plasma samples thereafter were taken and examined. Most of the tested agents failed to lower Lp(a) levels, and, in fact, in some instances, Lp(a) levels appeared to rise, possibly due to stimulation of Lp(a) production. The authors identified only two agents, namely neomycin and niacin, that decreased both LDL and Lp(a) levels. These agents only lower Lp(a) to a limited extent and because of this, as well as toxic side effects, do not appear to present a viable therapeutic avenue.
A need, therefore, exists for an effective method and associated agents for decreasing plasma Lp(a) levels.
The role of lipoprotein(a) has been studied in patients suffering from ischemic cerebrovascular disease and it has been determined they have significantly higher levels of lipoprotein(a), lipids carried by intermediate-density proteins, low-density lipoprotein cholesterol, and lower levels of high-density lipoproteins than control subjects. These then are major risk factors for ischemic cerebrovascular disease (Pedro-Botck, Stroke, 1992;23(11):1556-1562).
Lipoprotein(a) is a genetic, independent, and critical risk factor for ischemic stroke, especially in young adults (Nagayama, Stroke, 1994;25(1):74-78).
High serum lipoprotein(a) levels are an independent risk factor in the development of cerebral infarction (Shintani, Stroke, 1993;24(7):965-969.
Elevated plasma levels of Lp(a) lipoprotein have been linked to the development of premature atherosclerosis in coronary circulation (Valentine, Arch. Intern. Med., 1994;154:801-806).
The prevention of restenosis after percutaneous transluminal coronary angioplasty by reducing lipoprotein(a) levels with low-density lipoprotein apheresis is reported in Daida, Am. J. Card., 1994;73(15):1037-1040.
Serum Lp(a) is an independent factor associated with stenosis of saphenous vein grafts (Hoff, Circulation, 1988;77(6):1238-1243.